Anesthesia is extremely safe. Anesthesiologists use sophisticated technology to monitor the vital signs of and to provide respiratory and cardiovascular support for patients undergoing surgical procedures. Historically, most anesthetics were performed using inhaled agents. The depth of anesthesia induced by an inhalational anesthetic depends primarily on the partial pressure (or gas tension) of the anesthetic in the brain, and the rate of induction and recovery from anesthesia depends on the rate of change of partial pressure in the brain. The depth of anesthesia reflects the degree of blockade of sensory, reflex, mental, and motor functions, which can be achieved by using either inhalational or intravenous (IV) anesthetics, or combination of both agents. With inhalation agents, the concentration of drug delivered can be precisely metered and the variation between patients in the depth of anesthesia resulting from known concentrations of inhaled agents is relatively narrow, permitting the anesthesiologist to confidently assume a particular level of anesthesia based on the concentration of anesthetic gas delivered. Occasionally, this is not the case, and patients have recall of events that occurred during the surgical procedure. Recall is usually not a significant issue, however, in instances where a muscle relaxant is also given, rendering the patient paralyzed, an inadequate depth of anesthesia may result in the patient perceiving pain and being unable to alert the anesthesiologist. Also, the patient may remember conversation or other unpleasant events during his surgery. This rare, but dramatic event can be psychologically devastating to a patient. Because of these events, and the desire to more closely titrate the depth of anesthesia, a number of devices have been developed that purport to monitor a patient's depth of anesthesia by processing electrical signals produced by the brain. Studies have shown these technologies tend to be imprecise, and anesthetic agent specific. A more specific method of determining depth of anesthesia, or alternatively the blood concentration of anesthetic agents is desirable. Recently other methods of providing anesthesia, including IV anesthesia, have been popularized, and offer advantages over inhalation anesthetics.
Among the newer anesthetic techniques is total IV anesthesia (TIVA) which uses IV agents in place of the conventional vaporized inhalants. Unlike inhaled anesthetics, IV anesthetics produced a wider range of anesthesia for a specific drug dosage (less predictable), owing at least in part to interactions with other drugs, competition for binding sites in the blood and other body tissues, and genetic variation in the enzymes responsible for drug metabolism. At present, a major impediment to the wider use of IV anesthetics, rather than inhaled anesthetics, has been the inability to precisely determine the quantity of drug required to provide a sufficient “depth of anesthesia” without accumulating an excessive amount.
Propofol, for example, is an agent that is widely used as a short acting IV anesthetic. Its physiochemical properties are hydrophobic and volatile. It is usually administered as a constant IV infusion in order to deliver and maintain a specific plasma concentration. Although the metabolism is mainly hepatic and rapid, there is significant interpatient variability in the plasma concentration achieved with a known dose. However, the depth of anesthesia for a known plasma concentration is far less variable and it is therefore highly desirable to be able to evaluate plasma concentrations in real time to accurately maintain anesthetic efficacy. [“A Simple Method for Detecting Plasma Propofol,” Akihiko Fujita, MD, et al., Feb. 25, 2000, International Anesthesia Research Society]. The authors describe a means to measure plasma rather than total propofol using headspace—GC with solid phase microextraction. This is preferable since plasma (free) propofol is responsible for the anesthetic effect. Prior methods of monitoring propofol concentration in blood include high performance liquid chromatography (HPLC) and gas chromatography (GC). It has been reported that 97%-99% of propofol is bound with albumin and red blood cells after IV injection, and the remainder exists in blood as a free type. HPLC and GC detect the total propofol concentration, which does not correlate as well with the anesthetic effect as the plasma propofol level.
Propofol may also be monitored in urine. Metabolic processes control the clearance of propofol from the body, with the liver being the principal eliminating organ. [“First-pass Uptake and Pulmonary Clearance of Propofol,” Jette Kuipers, et al., Anesthesiology, V91, No.6, December 1999]. In a study, 88% of the dose of propofol was recovered in urine as hydroxylated and conjugated metabolites.
The aim of any dosage regimen in anesthesia is to titrate the delivery rate of a drug to achieve the desired pharmacolgic effect for any individual patient while minimizing the unwanted toxic side effects. Certain drugs such as propofol, afentanil and remifentanil have a close relationship between blood concentration and effect; thus, the administration of the drug can be improved by basing the dosage regimen on the pharmacokinetics of the agent. [Kenny, Gavin, Target-Controlled Infusions—Pharmacokinetics and Pharmodynamic Variations, http://www.anaesthesiologie.med.unierlangen.de/esctaic97/a_Kenny.htm]. Target controlled infusion (TCI) is one means for administering an intravenous anesthesia agent using a computer to control the infusion pump. Using a computer with a pharmacokinetic program permits control of a desired plasma concentration of an agent, such as propofol. The systems do not sample the blood in real-time, but use previously acquired population kinetics to provide a best estimate of the predicted blood concentration. However, even if TCI systems produced the exact target concentrations of blood concentration, it would not be possible to know if that concentration was satisfactory for each individual patient and for different points during the surgical procedure.
Among the technologies used to process and monitor electrical brain signal is BIS (Bispectral Index Monitor) monitoring of electroencephalography (EEG) data. It is an indirect monitor of depth of anesthesia. The BIS monitor translates EEG waves from the brain into a single number—depicting the depth of anesthesia on a scale from 1 to 100. In addition, neural networks have been used to classify sedation concentration from the power spectrum of the EEG signal. However, this technology is costly and not entirely predictive.
Artificial neural networks have also been developed which use the patient's age, weight, heart rate, respiratory rate, and blood pressure to predict depth of anesthesia. The networks integrate physiological signals and extract meaningful information. Certain systems use mid-latency auditory evoked potentials (MLAEP) which are wavelet transformed and fed into an artificial neural network for classification in determining the anesthesia depth. [Depth of Anesthesia Estimating & Propofol Delivery System, by Johnnie W. Huang, et al., Aug. 1, 1996, http://www.rpi.edu/˜royr/roy_descpt.html].
An apparatus and method for total intravenous anesthesia delivery is also disclosed in U.S. Pat. No. 6,186,977 to Andrews. This patent describes a method in which the patient is monitored using at least one of electrocardiogram (EKG), a blood oxygen monitor, a blood carbon dioxide monitor, inspiration/expiration oxygen, inspiration/expiration carbon dioxide, a blood pressure monitor, a pulse rate monitor, a respiration rate monitor, and a patient temperature monitor.
Accordingly, there is a need in the art for a more predictive method and apparatus for the non-invasive detection of drug concentration in blood, especially anesthetic agents.